Gene Summary

Gene:PTPRG; protein tyrosine phosphatase receptor type G
Summary:The protein encoded by this gene is a member of the protein tyrosine phosphatase (PTP) family. PTPs are known to be signaling molecules that regulate a variety of cellular processes including cell growth, differentiation, mitotic cycle, and oncogenic transformation. This PTP possesses an extracellular region, a single transmembrane region, and two tandem intracytoplasmic catalytic domains, and thus represents a receptor-type PTP. The extracellular region of this PTP contains a carbonic anhydrase-like (CAH) domain, which is also found in the extracellular region of PTPRBETA/ZETA. This gene is located in a chromosomal region that is frequently deleted in renal cell carcinoma and lung carcinoma, thus is thought to be a candidate tumor suppressor gene. [provided by RefSeq, Jul 2008]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:receptor-type tyrosine-protein phosphatase gamma
Source:NCBIAccessed: 01 September, 2019


What does this gene/protein do?
Show (6)

Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 02 September 2019 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Up-Regulation
  • Zeranol
  • Virus Integration
  • Cancer Gene Expression Regulation
  • Epigenetics
  • CpG Islands
  • Molecular Sequence Data
  • Translocation
  • Cancer DNA
  • Tamoxifen
  • Childhood Cancer
  • Mutation
  • Base Sequence
  • TNF
  • Down-Regulation
  • ras Proteins
  • Estrogen Receptors
  • Skin Cancer
  • Tumor Suppressor Gene
  • Chromosome 3
  • Messenger RNA
  • Siblings
  • Xenograft Models
  • Tyrosine
  • Validation Studies as Topic
  • DNA Methylation
  • Receptor-Like Protein Tyrosine Phosphatases, Class 5
  • Polymerase Chain Reaction
  • Tumor Suppressor Proteins
  • Signal Transduction
  • Nerve Tissue Proteins
  • Acid Anhydride Hydrolases
  • Sensitivity and Specificity
  • Neoplasm Proteins
  • Cell Proliferation
  • Proteins
  • Breast Cancer
  • Biomarkers, Tumor
  • Protein Tyrosine Phosphatases
  • Acute Lymphocytic Leukaemia
Tag cloud generated 01 September, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (3)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: PTPRG (cancer-related)

Yu C, Tian F, Liu J, et al.
Circular RNA cMras inhibits lung adenocarcinoma progression via modulating miR-567/PTPRG regulatory pathway.
Cell Prolif. 2019; 52(3):e12610 [PubMed] Related Publications
OBJECTIVES: Circular RNA, a type of RNA formed by a covalently closed loop, possesses sophisticated abilities of gene regulation in tumorigenesis and metastasis. However, the role of circRNAs on lung adenocarcinoma (LUAD) remains largely unknown.
MATERIALS AND METHODS: The role of cMras was examined both in vitro and in vivo. cMras expression in LUAD tissues was determined by quantitative real-time PCR (qRT-PCR). Downstream targets of cMras were predicted by bioinformatics tools and confirmed by RNA immunoprecipitation assay and luciferase assay. qRT-PCR and western blot assay were used to detect the expression of specific targets.
RESULTS: Thirty-six paired LUAD and healthy tissues were collected and cMras resulted significantly downregulated in cancerous tissues. Its expression was negatively associated with tumour stages. cMras overexpression suppressed LUAD growth and metastasis, while endogenous cMras silencing resulted in the opposite effects. Bioinformatics analysis and experimental evidence confirmed that cMras was a sponge of miRNA-567 and released its direct target, PTPRG. cMras overexpression decreased miR-567 expression and subsequently increased PTPRG expression, while increased miRNA-567 expression blocked the effects induced by cMras. Moreover, PTPRG was downregulated in LUAD and patients with low PTPRG expression exhibited significantly poor prognosis. These results suggested that cMras/miR-567/PTPRG regulatory pathway might be associated to LUAD tumorigenesis and development.
CONCLUSIONS: A novel circular RNA cMras and its functions were identified, discovering a cMras/miR-567/PTPRG regulatory pathway in LUAD tumorigenesis and development.

Antony J, Zanini E, Kelly Z, et al.
The tumour suppressor OPCML promotes AXL inactivation by the phosphatase PTPRG in ovarian cancer.
EMBO Rep. 2018; 19(8) [PubMed] Free Access to Full Article Related Publications
In ovarian cancer, the prometastatic RTK AXL promotes motility, invasion and poor prognosis. Here, we show that reduced survival caused by AXL overexpression can be mitigated by the expression of the GPI-anchored tumour suppressor OPCML Further, we demonstrate that AXL directly interacts with OPCML, preferentially so when AXL is activated by its ligand Gas6. As a consequence, AXL accumulates in cholesterol-rich lipid domains, where OPCML resides. Here, phospho-AXL is brought in proximity to the lipid domain-restricted phosphatase PTPRG, which de-phosphorylates the RTK/ligand complex. This prevents AXL-mediated transactivation of other RTKs (cMET and EGFR), thereby inhibiting sustained phospho-ERK signalling, induction of the EMT transcription factor Slug, cell migration and invasion. From a translational perspective, we show that OPCML enhances the effect of the phase II AXL inhibitor R428

Kostas M, Haugsten EM, Zhen Y, et al.
Protein Tyrosine Phosphatase Receptor Type G (PTPRG) Controls Fibroblast Growth Factor Receptor (FGFR) 1 Activity and Influences Sensitivity to FGFR Kinase Inhibitors.
Mol Cell Proteomics. 2018; 17(5):850-870 [PubMed] Free Access to Full Article Related Publications
Recently, FGFR1 was found to be overexpressed in osteosarcoma and represents an important target for precision medicine. However, because targeted cancer therapy based on FGFR inhibitors has so far been less efficient than expected, a detailed understanding of the target is important. We have here applied proximity-dependent biotin labeling combined with label-free quantitative mass spectrometry to identify determinants of FGFR1 activity in an osteosarcoma cell line. Many known FGFR interactors were identified (

Lei L, Ding L, Su J, et al.
Attenuated expression of MTR in both prenatally androgenized mice and women with the hyperandrogenic phenotype of PCOS.
PLoS One. 2017; 12(12):e0187427 [PubMed] Free Access to Full Article Related Publications
Polycystic ovary syndrome (PCOS) is a common endocrine, metabolic and heterogeneous disorder in women of reproductive age, the exact etiology of which remains unknown. To unravel the molecular mechanisms underlying the hyperandrogenic phenotype of PCOS, prenatally androgenized (PNA) mice were used to mimic this phenotype in women with PCOS. Using microarray analysis, 1188 differentially expressed genes, including 671 upregulated and 517 downregulated genes, were identified in ovaries from PNA mice. Five differentially expressed genes (Aldh1a7, Bhmt, Mtr, Nrcam, Ptprg) were validated, and decreased MTR expression was shown in ovaries of PNA mice. In addition, results from qRT-PCR showed decreased MTR expression in granulosa cells (GCs) from women with the hyperandrogenic phenotype of PCOS. Serum levels of S-adenosyl methionine (SAM), the downstream product of MTR, were also decreased in PNA mice and women with the hyperandrogenic phenotype of PCOS. Our study provides evidence that the hyperandrogenic phenotype of PCOS is linked to abnormal folate one-carbon metabolism.

Vezzalini M, Mafficini A, Tomasello L, et al.
A new monoclonal antibody detects downregulation of protein tyrosine phosphatase receptor type γ in chronic myeloid leukemia patients.
J Hematol Oncol. 2017; 10(1):129 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Protein tyrosine phosphatase receptor gamma (PTPRG) is a ubiquitously expressed member of the protein tyrosine phosphatase family known to act as a tumor suppressor gene in many different neoplasms with mechanisms of inactivation including mutations and methylation of CpG islands in the promoter region. Although a critical role in human hematopoiesis and an oncosuppressor role in chronic myeloid leukemia (CML) have been reported, only one polyclonal antibody (named chPTPRG) has been described as capable of recognizing the native antigen of this phosphatase by flow cytometry. Protein biomarkers of CML have not yet found applications in the clinic, and in this study, we have analyzed a group of newly diagnosed CML patients before and after treatment. The aim of this work was to characterize and exploit a newly developed murine monoclonal antibody specific for the PTPRG extracellular domain (named TPγ B9-2) to better define PTPRG protein downregulation in CML patients.
METHODS: TPγ B9-2 specifically recognizes PTPRG (both human and murine) by flow cytometry, western blotting, immunoprecipitation, and immunohistochemistry.
RESULTS: Co-localization experiments performed with both anti-PTPRG antibodies identified the presence of isoforms and confirmed protein downregulation at diagnosis in the Philadelphia-positive myeloid lineage (including CD34
CONCLUSIONS: The availability of this unique antibody permits its evaluation for clinical application including the support for diagnosis and follow-up of these disorders. Evaluation of PTPRG as a potential therapeutic target is also facilitated by the availability of a specific reagent capable to specifically detect its target in various experimental conditions.

Liu M, Yang R, Urrehman U, et al.
MiR-19b suppresses PTPRG to promote breast tumorigenesis.
Oncotarget. 2016; 7(39):64100-64108 [PubMed] Free Access to Full Article Related Publications
Protein tyrosine phosphatase receptor type G (PTPRG) is an important tumor suppressor gene in multiple human cancers. In this study, we found that PTPRG protein levels were downregulated in breast cancer tissues while the mRNA levels varied irregularly, implying a post-transcriptional mechanism was involved. Because microRNAs are powerful post-transcriptional regulators of gene expression, we used bioinformatics analysis to search for microRNAs that potentially targets PTPRG in the setting of breast cancer. We identified two specific binding sites for miR-19b in the 3'-untranslated region of PTPRG. We further identified an inverse correlation between miR-19b and PTPRG protein levels, but not mRNA levels, in human breast cancer tissues. By overexpressing or knocking down miR-19b in MCF-7 cells and MDA-231 cells, we experimentally confirmed that miR-19b directly suppresses PTPRG expression. Furthermore, we determined that the inhibition of PTPRG by miR-19b leads to increased proliferation, stimulated cell migration and reduced apoptosis. Taken together, our findings provide the first evidence that miR-19b inhibits PTPRG expression to promote tumorigenesis in human breast cancer.

Iranpour M, Soudyab M, Geranpayeh L, et al.
Expression analysis of four long noncoding RNAs in breast cancer.
Tumour Biol. 2016; 37(3):2933-40 [PubMed] Related Publications
Breast cancer is a molecularly heterogeneous disease which necessitates a search for markers to provide a more specific classification of this disorder. Long noncoding RNAs as the important subset of noncoding transcripts have been shown to be involved in tumorigenic processes. So, they may be used as markers for early detection of cancer and evaluation of cancer prognosis. In addition, they can be applied as therapeutic targets. In this study, we analyzed expression of four long noncoding RNAs (lncRNAs) namely SOX2OT, PTPRG-AS1, ANRASSF1, and ANRIL in 38 breast cancer tissues and their adjacent noncancerous tissues (ANCTs). ANRASSF1 expression was not detected in any noncancerous tissue. All lncRNAs showed significant overexpression in tumor tissues compared with ANCTs. No association was found between gene expressions and individual clinical data such as tumor stage, grade, size and hormone receptor status except for ANRASSF1 expression and Her2/neu status. In addition, ANRASSF1 and ANRIL expressions were significantly higher in triple negative samples. This study suggests a putative role for these lncRNAs in breast cancer and implies that they can be used as potential cancer biomarkers.

Cheung AK, Ip JC, Chu AC, et al.
PTPRG suppresses tumor growth and invasion via inhibition of Akt signaling in nasopharyngeal carcinoma.
Oncotarget. 2015; 6(15):13434-47 [PubMed] Free Access to Full Article Related Publications
Protein Tyrosine Phosphatase, Receptor Type G (PTPRG) was identified as a candidate tumor suppressor gene in nasopharyngeal carcinoma (NPC). PTPRG induces significant in vivo tumor suppression in NPC. We identified EGFR as a PTPRG potential interacting partner and examined this interaction. Dephosphorylation of EGFR at EGFR-Y1068 and -Y1086 sites inactivated the PI3K/Akt signaling cascade and subsequent down-regulation of downstream pro-angiogenic and -invasive proteins (VEGF, IL6, and IL8) and suppressed tumor cell proliferation, angiogenesis, and invasion. The effect of Akt inhibition in NPC cells was further validated by Akt knockdown experiments in the PTPRG-down-regulated NPC cell lines. Our results suggested that inhibition of Akt in NPC cells induces tumor suppression at both the in vitro and in vivo levels, and also importantly, in vivo metastasis. In conclusion, we confirmed the vital role of PTPRG in inhibiting Akt signaling with the resultant suppression of in vivo tumorigenesis and metastasis.

Kiflemariam S, Ljungström V, Pontén F, Sjöblom T
Tumor vessel up-regulation of INSR revealed by single-cell expression analysis of the tyrosine kinome and phosphatome in human cancers.
Am J Pathol. 2015; 185(6):1600-9 [PubMed] Related Publications
The tyrosine kinome and phosphatome harbor oncogenes and tumor suppressor genes and important regulators of angiogenesis and tumor stroma formation. To provide a better understanding of their potential roles in cancer, we analyzed the expression of 85 tyrosine kinases and 42 tyrosine phosphatases by in situ hybridization 48 human normal and 24 tumor tissue specimens. Nine-tenths of the assessed transcripts had tumor cell expression concordant with expression array databases. Further, pan-cancer expression of AATK, PTPRK, and PTPRU and expression of PTPRS in a subset of tumors were observed. To demonstrate tumor subcompartment resolution, we validated the predicted tumor stroma-specific markers HTRA1, HTRA3, MXRA5, MXRA8, and SERPING1 in situ. In addition to known vascular and stromal markers such as PDGFRB, we observed stromal expression of PTK6 and TNS1 and vascular expression of INSR, PTPRF, PTPRG, PTPRU, and TNS1, of which INSR emerged as a tumor-specific vessel marker. This study demonstrates the feasibility of large-scale analyses to chart the transcriptome in situ in human cancers and their ability to identify novel cancer biomarkers.

Linhares ND, Freire MC, Cardenas RG, et al.
Modulation of expressivity in PDGFRB-related infantile myofibromatosis: a role for PTPRG?
Genet Mol Res. 2014; 13(3):6287-92 [PubMed] Related Publications
Infantile myofibromatosis is a rare genetic disorder characterized by the development of benign tumors in the skin, muscle, bone, and viscera. The molecular pathogenesis is still incompletely known. An autosomal dominant form had been reported as causally related with mutations in the gene for platelet-derived growth factor receptor beta (PDGFRB). We report here two siblings with infantile myofibromatosis and with a PDGFRB mutation identified by exome sequence analysis. However, the unaffected mother also had the same PDGFRB mutation. We showed that both children had also inherited from their healthy father a heterozygous mutation in the gene for receptor protein tyrosine phosphatase gamma (PTPRG), an enzyme known to dephosphorylate PDGFRB. We suggest that in this family, the additional mutation in PTPRG may explain the full phenotypic penetrance in the siblings affected, in comparison with the unaffected mother.

Xiao J, Lee ST, Xiao Y, et al.
PTPRG inhibition by DNA methylation and cooperation with RAS gene activation in childhood acute lymphoblastic leukemia.
Int J Cancer. 2014; 135(5):1101-9 [PubMed] Free Access to Full Article Related Publications
While the cytogenetic and genetic characteristics of childhood acute lymphoblastic leukemias (ALL) are well studied, less clearly understood are the contributing epigenetic mechanisms that influence the leukemia phenotype. Our previous studies and others identified gene mutation (RAS) and DNA methylation (FHIT) to be associated with the most common cytogenetic subgroup of childhood ALL, high hyperdiploidy (having five more chromosomes). We screened DNA methylation profiles, using a genome-wide high-dimension platform of 166 childhood ALLs and 6 normal pre-B cell samples and observed a strong association of DNA methylation status at the PTPRG locus in human samples with levels of PTPRG gene expression as well as with RAS gene mutation status. In the 293 cell line, we found that PTPRG expression induces dephosphorylation of ERK, a downstream RAS target that may be critical for mutant RAS-induced cell growth. In addition, PTPRG expression is upregulated by RAS activation under DNA hypomethylating conditions. An element within the PTPRG promoter is bound by the RAS-responsive transcription factor RREB1, also under hypomethylating conditions. In conclusion, we provide evidence that DNA methylation of the PTPRG gene is a complementary event in oncogenesis induced by RAS mutations. Evidence for additional roles for PTPR family member genes is also suggested. This provides a potential therapeutic target for RAS-related leukemias as well as insight into childhood ALL etiology and pathophysiology.

Chatterton Z, Morenos L, Mechinaud F, et al.
Epigenetic deregulation in pediatric acute lymphoblastic leukemia.
Epigenetics. 2014; 9(3):459-67 [PubMed] Free Access to Full Article Related Publications
Similar to most cancers, genome-wide DNA methylation profiles are commonly altered in pediatric acute lymphoblastic leukemia (ALL); however, recent observations highlight that a large portion of malignancy-associated DNA methylation alterations are not accompanied by related gene expression changes. By analyzing and integrating the methylome and transcriptome profiles of pediatric B-cell ALL cases and primary tissue controls, we report 325 genes hypermethylated and downregulated and 45 genes hypomethylated and upregulated in pediatric B-cell ALL, irrespective of subtype. Repressed cation channel subunits and cAMP signaling activators and transducers are overrepresented, potentially indicating a reduced cellular potential to receive and propagate apoptotic signals. Furthermore, we report specific DNA methylation alterations with concurrent gene expression changes within individual ALL subtypes. The ETV6-RUNX1 translocation was associated with downregulation of ASNS and upregulation of the EPO-receptor, while Hyperdiploid patients (> 50 chr) displayed upregulation of B-cell lymphoma (BCL) members and repression of PTPRG and FHIT. In combination, these data indicate genetically distinct B-cell ALL subtypes contain cooperative epimutations and genome-wide epigenetic deregulation is common across all B-cell ALL subtypes.

Stevenson WS, Best OG, Przybylla A, et al.
DNA methylation of membrane-bound tyrosine phosphatase genes in acute lymphoblastic leukaemia.
Leukemia. 2014; 28(4):787-93 [PubMed] Related Publications
Aberrant DNA promoter methylation with associated gene silencing is a common epigenetic abnormality in acute lymphoblastic leukaemia (ALL) and is associated with poor survival. We have identified a family of transmembrane tyrosine phosphatase proteins as targets of hypermethylation in ALL and high-grade B cell lymphoma and demonstrated that this abnormal methylation correlates with transcript expression. PTPRG was methylated in 63% of ALL samples, PTPRK in 47%, PTPRM in 64% and PTPRO in 54% of cases, with most ALL samples containing methylation at multiple phosphatase loci. PTPRK promoter methylation was associated with a decreased overall survival in the cohort. Restoration of PTPRK transcript levels in leukaemia cells, where phosphatase transcript was silenced, reduced cell proliferation, inhibited colony formation and increased sensitivity to cytotoxic chemotherapy. These biological changes were associated with a reduction in levels of phosphorylated Erk1/2, Akt, STAT3 and STAT5 suggesting functional phosphatase activity after transcript re-expression. Methylation of the phosphatase promoters was reversible with decitabine and a histone deacetylase inhibitor, suggesting that PTPRK-mediated cell signalling pathways may be targeted with epigenetic therapies in lymphoid malignancy.

Laczmanska I, Sasiadek MM
Tyrosine phosphatases as a superfamily of tumor suppressors in colorectal cancer.
Acta Biochim Pol. 2011; 58(4):467-70 [PubMed] Related Publications
Phosphorylation and dephosphorylation processes catalyzed by numerous kinases and phosphorylases are essential for cell homeostasis and may lead to disturbances in a variety of vital cellular pathways, such as cell proliferation and differentiation, and thus to complex diseases including cancer. As over 80 % of all oncogenes encode protein tyrosine kinases (PTKs), protein tyrosine phosphatases (PTPs), which can reverse the effects of tyrosine kinases, are very important tumor suppressors. Alterations in tyrosine kinase and phosphatase genes including point mutations, changes in epigenetic regulation, as well as chromosomal aberrations involving regions critical to these genes, are frequently observed in a variety of cancers. Colorectal cancer (CRC) is one of the most common cancers in humans. CRCs occur in a familial (about 15 % of all cases), hereditary (about 5%) and sporadic (almost 75-80 %) form. As genetic-environmental interrelations play an important role in the susceptibility to sporadic forms of CRCs, many studies are focused on genetic alterations in such tumors. Mutational analysis of the tyrosine phosphatome in CRCs has identified somatic mutations in PTPRG, PTPRT, PTPN3, PTPN13 and PTPN14. The majority of these mutations result in a loss of protein function. Also, alterations in the expression of these genes, such as decreased expression of PTPRR, PTPRO, PTPRG and PTPRD, mediated by epigenetic mechanisms have been observed in a variety of tumors. Since cancer is a social and global problem, there will be a growing number of studies on alterations in the candidate cancer genes, including protein kinases and phosphatases, to determine the origin, biology and potential pathways for targeted anticancer therapy.

Lin G, Aranda V, Muthuswamy SK, Tonks NK
Identification of PTPN23 as a novel regulator of cell invasion in mammary epithelial cells from a loss-of-function screen of the 'PTP-ome'.
Genes Dev. 2011; 25(13):1412-25 [PubMed] Free Access to Full Article Related Publications
We used an RNAi-mediated loss-of-function screen to study systematically the role of the protein tyrosine phosphatase (PTP) superfamily of enzymes in mammary epithelial cell motility in the absence or presence of the oncoprotein tyrosine kinase ERBB2. We report that although shRNAs directed against most of the PTP family were without effect, suppression of three PTPs-PRPN23, PTPRG, and PTPRR-enhanced cell motility. Furthermore, we found that suppression of PTPN23, but not PTPRG or PTPRR, induced cell invasion. Suppression of PTPN23 increased E-cadherin internalization, impaired early endosome trafficking of E-cadherin, induced the expression of mesenchymal proteins, and caused cell scattering. The activity of SRC and β-catenin was elevated when PTPN23 was suppressed. Moreover, we identified SRC, E-cadherin, and β-catenin as direct substrates of PTPN23. Inhibition of SRC with the small molecular inhibitor SU6656 blocked the effects of PTPN23 depletion. These findings suggest that loss of PTPN23 may increase the activity of SRC and the phosphorylation status of the E-cadherin/β-catenin signaling complex to promote tumor growth and invasive behavior in breast cancer. In addition, our studies highlight functional specificity among PTPs and reveal new roles for PTPs in mammary epithelial cell biology.

van Roon EH, de Miranda NF, van Nieuwenhuizen MP, et al.
Tumour-specific methylation of PTPRG intron 1 locus in sporadic and Lynch syndrome colorectal cancer.
Eur J Hum Genet. 2011; 19(3):307-12 [PubMed] Free Access to Full Article Related Publications
DNA methylation is a hallmark in a subset of right-sided colorectal cancers. Methylation-based screening may improve prevention and survival rate for this type of cancer, which is often clinically asymptomatic in the early stages. We aimed to discover prognostic or diagnostic biomarkers for colon cancer by comparing DNA methylation profiles of right-sided colon tumours and paired normal colon mucosa using an 8.5 k CpG island microarray. We identified a diagnostic CpG-rich region, located in the first intron of the protein-tyrosine phosphatase gamma gene (PTPRG) gene, with altered methylation already in the adenoma stage, that is, before the carcinoma transition. Validation of this region in an additional cohort of 103 sporadic colorectal tumours and 58 paired normal mucosa tissue samples showed 94% sensitivity and 96% specificity. Interestingly, comparable results were obtained when screening a cohort of Lynch syndrome-associated cancers. Functional studies showed that PTPRG intron 1 methylation did not directly affect PTPRG expression, however, the methylated region overlapped with a binding site of the insulator protein CTCF. Chromatin immunoprecipitation (ChIP) showed that methylation of the locus was associated with absence of CTCF binding. Methylation-associated changes in CTCF binding to PTPRG intron 1 could have implications on tumour gene expression by enhancer blocking, chromosome loop formation or abrogation of its insulator function. The high sensitivity and specificity for the PTPRG intron 1 methylation in both sporadic and hereditary colon cancers support biomarker potential for early detection of colon cancer.

Della Peruta M, Martinelli G, Moratti E, et al.
Protein tyrosine phosphatase receptor type {gamma} is a functional tumor suppressor gene specifically downregulated in chronic myeloid leukemia.
Cancer Res. 2010; 70(21):8896-906 [PubMed] Related Publications
Chronic myelogenous leukemia (CML) is the most common myeloproliferative disease. Protein tyrosine phosphatase receptor type γ (PTPRG) is a tumor suppressor gene and a myeloid cell marker expressed by CD34(+) cells. Downregulation of PTPRG increases colony formation in the PTPRG-positive megakaryocytic cell lines MEG-01 and LAMA-84 but has no effect in the PTPRG-negative cell lines K562 and KYO-1. Its overexpression has an oncosuppressive effect in all these cell lines and is associated with myeloid differentiation and inhibition of BCR/ABL-dependent signaling. The intracellular domain of PTPRG directly interacts with BCR/ABL and CRKL, but not with signal transducers and activators of transcription 5. PTPRG is downregulated at the mRNA and protein levels in leukocytes of CML patients in both peripheral blood and bone marrow, including CD34(+) cells, and is reexpressed following molecular remission of disease. Reexpression was associated with a loss of methylation of a CpG island of PTPRG promoter occurring in 55% of the patients analyzed. In K562 cell line, the DNA hypomethylating agent 5-aza-2'-deoxycytidine induced PTPRG expression and caused an inhibition of colony formation, partially reverted by downregulation of PTPRG expression. These findings establish, for the first time, PTPRG as a tumor suppressor gene involved in the pathogenesis of CML, suggesting its use as a potential diagnostic and therapeutic target.

Helmbold P, Lahtz C, Enk A, et al.
Frequent occurrence of RASSF1A promoter hypermethylation and Merkel cell polyomavirus in Merkel cell carcinoma.
Mol Carcinog. 2009; 48(10):903-9 [PubMed] Related Publications
Merkel cell carcinoma (MCC) is one of the most aggressive cancers of the skin. It has recently been reported that integration of a Merkel cell polyomavirus (MCPyV) in receptor tyrosine phosphates type G (PTPRG) gene occurs in MCC, and that viral infections are associated with epigenetic silencing of tumor suppressor genes (TSG) in cancer. To examine whether a correlation between TSG inactivation and viral infection can be found in MCC, we investigated the promoter hypermethylation of RASSF1A, TP73, PTPRG, FHIT, and CDKN2A and the presence of MCPyV and SV40 in 98 MCC by PCR. Hypermethylation of RASSF1A was frequently found in 42 of 83 (51%) of MCC. Methylation of CDKN2A was present in 9 of 41 (22%) of MCC. Hypermethylation of TP73 (0%), PTPRG (4%), and FHIT (0%) was infrequent in MCC. Interestingly, MCPyV was found in 90 of 98 (92%) MCC, however, no SV40 signal was detected. No correlation between TSG hypermethylation and viral infection was found. Our results show frequent hypermethylation of RASSF1A and the presence of MCPyV in primary MCC, and that these events may contribute to the pathogenesis of MCC.

Guggenheim ER, Xu D, Zhang CX, et al.
Photoaffinity isolation and identification of proteins in cancer cell extracts that bind to platinum-modified DNA.
Chembiochem. 2009; 10(1):141-57 [PubMed] Free Access to Full Article Related Publications
The activity of the anticancer drug cisplatin is a consequence of its ability to bind DNA. Platinum adducts bend and unwind the DNA duplex, creating recognition sites for nuclear proteins. Following DNA damage recognition, the lesions will either be repaired, facilitating cell viability, or if repair is unsuccessful and the Pt adduct interrupts vital cellular functions, apoptosis will follow. With the use of the benzophenone-modified cisplatin analogue Pt-BP6, 25 bp DNA duplexes containing either a 1,2-d(G*pG*) intrastrand or a 1,3-d(G*pTpG*) intrastrand crosslink were synthesized, where the asterisks designate platinated nucleobases. Proteins having affinity for these platinated DNAs were photocrosslinked and identified in cervical, testicular, pancreatic and bone cancer-cell nuclear extracts. Proteins identified in this manner include the DNA repair factors RPA1, Ku70, Ku80, Msh2, DNA ligase III, PARP-1, and DNA-PKcs, as well as HMG-domain proteins HMGB1, HMGB2, HMGB3, and UBF1. The latter strongly associate with the 1,2-d(G*pG*) adduct and weakly or not at all with the 1,3-d(G*pTpG*) adduct. The nucleotide excision repair protein RPA1 was photocrosslinked only by the probe containing a 1,3-d(G*pTpG*) intrastrand crosslink. The affinity of PARP-1 for platinum-modified DNA was established using this type of probe for the first time. To ensure that the proteins were not photocrosslinked because of an affinity for DNA ends, a 90-base dumbbell probe modified with Pt-BP6 was investigated. Photocrosslinking experiments with this longer probe revealed the same proteins, as well as some additional proteins involved in chromatin remodeling, transcription, or repair. These findings reveal a more complete list of proteins involved in the early steps of the mechanism of action of the cisplatin and its close analogue carboplatin than previously was available.

Cheung AK, Lung HL, Hung SC, et al.
Functional analysis of a cell cycle-associated, tumor-suppressive gene, protein tyrosine phosphatase receptor type G, in nasopharyngeal carcinoma.
Cancer Res. 2008; 68(19):8137-45 [PubMed] Related Publications
Functional studies to identify the potential role of a chromosome 3p14-21 gene, protein tyrosine phosphatase receptor type G (PTPRG), were performed. PTPRG was identified as a candidate tumor suppressor gene (TSG) in nasopharyngeal carcinoma (NPC) by differential gene profiling of tumorigenic and nontumorigenic NPC chromosome 3 microcell hybrids (MCH). Down-regulation of this gene was found in tumor segregants when compared with their corresponding tumor-suppressive MCHs, as well as in NPC cell lines and tumor biopsies. Promoter hypermethylation and loss of heterozygosity were found to be important mechanisms contributing to PTPRG silencing. PTPRG overexpression in NPC cell lines induces growth suppression and reduced anchorage-independent growth in vitro. This is the first study to use a tetracycline-responsive vector expression system to study PTPRG stable transfectants. Results indicate its ability to induce significant tumor growth suppression in nude mice under conditions activating transgene expression. These studies now provide functional evidence indicating critical interactions of PTPRG in the extracellular matrix milieu induce cell arrest and changes in cell cycle status. This is associated with inhibition of pRB phosphorylation through down-regulation of cyclin D1. These novel findings enhance our current understanding of how PTPRG may contribute to tumorigenesis.

Feng H, Shuda M, Chang Y, Moore PS
Clonal integration of a polyomavirus in human Merkel cell carcinoma.
Science. 2008; 319(5866):1096-100 [PubMed] Free Access to Full Article Related Publications
Merkel cell carcinoma (MCC) is a rare but aggressive human skin cancer that typically affects elderly and immunosuppressed individuals, a feature suggestive of an infectious origin. We studied MCC samples by digital transcriptome subtraction and detected a fusion transcript between a previously undescribed virus T antigen and a human receptor tyrosine phosphatase. Further investigation led to identification and sequence analysis of the 5387-base-pair genome of a previously unknown polyomavirus that we call Merkel cell polyomavirus (MCV or MCPyV). MCV sequences were detected in 8 of 10 (80%) MCC tumors but only 5 of 59 (8%) control tissues from various body sites and 4 of 25 (16%) control skin tissues. In six of eight MCV-positive MCCs, viral DNA was integrated within the tumor genome in a clonal pattern, suggesting that MCV infection and integration preceded clonal expansion of the tumor cells. Thus, MCV may be a contributing factor in the pathogenesis of MCC.

Wang JF, Dai DQ
Metastatic suppressor genes inactivated by aberrant methylation in gastric cancer.
World J Gastroenterol. 2007; 13(43):5692-8 [PubMed] Free Access to Full Article Related Publications
AIM: To screen out the differentially methylated DNA sequences between gastric primary tumor and metastatic lymph nodes, test the methylation difference of gene PTPRG between primary gastric tumor and metastatic lymph nodes, and test the regulatory function of 5-aza-2'-deoxycytidine which is an agent with suppression on methylation and the level of methylation in gastric cancer cell line.
METHODS: Methylated DNA sequences in genome were enriched with methylated CpG islands amplification (MCA) to undergo representational difference analysis (RDA), with MCA production of metastatic lymph nodes as tester and that of primary tumor as driver. The obtained differentially methylated fragments were cloned and sequenced to acquire the base sequence, which was analyzed with bioinformatics. With methylation-specific PCR (MSP) and RT-PCR, methylation difference of gene PTPRG was detected between primary tumor and metastatic lymph nodes in 36 cases of gastric cancer. Methylation of gene PTPRG and its regulated expression were observed in gastric cancer cell line before and after being treated with methylation-suppressive agent.
RESULTS: Nineteen differentially methylated sequences were obtained and located at 5' end, exons, introns and 3' end, in which KL59 was observed to be located at 9p21 as the first exon of gene p16 and KL22 to be located at promoter region of PRPRG. KL22, as the probes, was hybridized with driver, tester and 3-round RDA products respectively with all positive signals except with the driver. Significant difference was observed in both methylation rate of gene PTPRG and PTPRG mRNA expression rate between primary tumor and metastatic lymph nodes. Demethylation of gene PTPRG, with recovered expression of PTPRG mRNA, was observed after gastric cancer cell line being treated with methylation-suppressive agent.
CONCLUSION: Difference exists in DNA methylation between primary tumor and metastatic lymph nodes of gastric cancer, with MCA-RDA as one of the good analytical methods. Significant difference exists in methylation of gene PTPRG between primary tumor and metastatic lymph nodes of gastric cancer. Methylation level in gastric cancer cell line can be decreased by 5-aza-2'-deoxycytidine, which is the methylation-suppressive agent, with PTPRG expression being recovered.

Choi YW, Bae SM, Kim YW, et al.
Gene expression profiles in squamous cell cervical carcinoma using array-based comparative genomic hybridization analysis.
Int J Gynecol Cancer. 2007 May-Jun; 17(3):687-96 [PubMed] Related Publications
Our aim was to identify novel genomic regions of interest and provide highly dynamic range information on correlation between squamous cell cervical carcinoma and its related gene expression patterns by a genome-wide array-based comparative genomic hybridization (array-CGH). We analyzed 15 cases of cervical cancer from KangNam St Mary's Hospital of the Catholic University of Korea. Microdissection assay was performed to obtain DNA samples from paraffin-embedded cervical tissues of cancer as well as of the adjacent normal tissues. The bacterial artificial chromosome (BAC) array used in this study consisted of 1440 human BACs and the space among the clones was 2.08 Mb. All the 15 cases of cervical cancer showed the differential changes of the cervical cancer-associated genetic alterations. The analysis limit of average gains and losses was 53%. A significant positive correlation was found in 8q24.3, 1p36.32, 3q27.1, 7p21.1, 11q13.1, and 3p14.2 changes through the cervical carcinogenesis. The regions of high level of gain were 1p36.33-1p36.32, 8q24.3, 16p13.3, 1p36.33, 3q27.1, and 7p21.1. And the regions of homozygous loss were 2q12.1, 22q11.21, 3p14.2, 6q24.3, 7p15.2, and 11q25. In the high level of gain regions, GSDMDC1, RECQL4, TP73, ABCF3, ALG3, HDAC9, ESRRA, and RPS6KA4 were significantly correlated with cervical cancer. The genes encoded by frequently lost clones were PTPRG, GRM7, ZDHHC3, EXOSC7, LRP1B, and NR3C2. Therefore, array-CGH analyses showed that specific genomic alterations were maintained in cervical cancer that were critical to the malignant phenotype and may give a chance to find out possible target genes present in the gained or lost clones.

Vezzalini M, Mombello A, Menestrina F, et al.
Expression of transmembrane protein tyrosine phosphatase gamma (PTPgamma) in normal and neoplastic human tissues.
Histopathology. 2007; 50(5):615-28 [PubMed] Related Publications
AIMS: To establish the conditions for protein tyrosine phosphatase gamma (PTPgamma) detection in paraffin tissues using two antibodies raised against its NH(2)- (anti-P4) and COOH-termini (gammaTL1); to analyse its expression in normal tissues and to perform an initial screening of neoplastic tissues.
METHODS AND RESULTS: Membranous and/or cytoplasmic PTPgamma expression was detected in the majority of epithelial cell types and in endocrine cells, with the highest expression in adrenal medulla, endocrine cells of the gastrointestinal tract and pancreatic islets. Both antibodies stained the thyroid follicular epithelium, but only anti-P4 antibody stained the colloid matrix, suggesting shedding/secretion of the PTPgamma extracellular domain. Marked loss of PTPgamma immunoreactivity was detected in subsets of ovarian (21%), breast (56%) and lung (80%) neoplasms. Conversely, cytoplasmic positivity was found in 37% of lymphomas, mainly of high-grade histotypes, while normal lymphocytes were negative. Brain tissue showed PTPgamma expression in a few neuronal and glial elements and PTPgamma was overexpressed in the majority of high-grade astrocytomas.
CONCLUSIONS: We have analysed PTPgamma expression in archival paraffin-embedded tissues for the first time, demonstrating particularly high expression in endocrine cells and both down- and up-regulation in neoplasia, the latter possibly reflecting the undifferentiated state of the neoplastic cells, suggesting a complex role for this phosphatase.

Lissandrini D, Vermi W, Vezzalini M, et al.
Receptor-type protein tyrosine phosphatase gamma (PTPgamma), a new identifier for myeloid dendritic cells and specialized macrophages.
Blood. 2006; 108(13):4223-31 [PubMed] Related Publications
Protein tyrosine phosphatase (PTPgamma) is a receptor-like molecule with a known role in murine hematopoiesis. We analyzed the regulation of PTPgamma expression in the human hematopoietic system, where it was detected in human peripheral blood monocytes and dendritic cells (DCs) of myeloid and plasmacytoid phenotypes. Its expression was maintained during in vitro monocyte differentiation to dendritic cells (moDC) and was further increased after maturation with bacterial lipopolysaccharide (LPS), CD40L, and TNFalpha. But PTPgamma was absent when monocytes from the same donor were induced to differentiate in macrophages. B and T lymphocytes did not express PTPgamma. Rather, PTPgamma mRNA was expressed in primary and secondary lymphoid tissues, and the highest expression was in the spleen. PTPgamma was detected by immunohistochemistry in subsets of myeloid-derived DCs and specialized macrophages (tingible bodies, sinus and alveolar macrophages). Classic macrophages in infective or reactive granulomatous reactions did not express PTPgamma. Increased PTPgamma expression was associated with a decreased ability to induce proliferation and interferon-gamma secretion in T cells by moDCs from patients with advanced pancreatic cancer. Taken together, these results indicate that PTPgamma is a finely regulated protein in DC and macrophage subsets in vitro and in vivo.

Chang HL, Sugimoto Y, Liu S, et al.
Keratinocyte growth factor (KGF) induces tamoxifen (Tam) resistance in human breast cancer MCF-7 cells.
Anticancer Res. 2006 May-Jun; 26(3A):1773-84 [PubMed] Related Publications
BACKGROUND: Both estrogen receptor-alpha (ER-alpha) and progesterone receptor (PR) are good prognostic factors and indicators of benefit from endocrine therapy in breast cancer patients. The relationship of the ER-alpha and PR status and the difference in clinical benefit from endocrine therapy in breast cancer is currently unclear. It has been suggested that keratinocyte growth factors (KGFs) are important regulatory factors in breast cancer. Our laboratory has demonstrated that KGF can act as an estromedin for the stimulation of breast cancer cell growth. Also, KGF stimulates aromatase activity in primary cultured human breast cells. This enzyme is a key to the conversion of androgens to estrogens. In the present study, ER-alpha, two estrogen-regulated genes, PR and PTPgamma, KGF and their relationship with endocrine resistance in human breast cancer cells were investigated.
MATERIALS AND METHODS: MCF-7 cells were treated with KGF (1, 5, 10, 20 ng/ml), KGF-13 (0.1, 1, 10 microM) or vehicles as control for 24 hours. KGF-13 is a potential receptor-binding pentapeptide constructed using the KGF peptide residues 101-105 (RTVAV) as a template, located within the beta 4--beta 5 loop. Total RNA were isolated and real-time PCR was employed to identify ER-alpha, PR and PTPgamma gene expressions in response to KGF and KGF-13. Western blot analysis was used to verify the levels of ER-alpha and PR protein, whereas immunohistochemical staining was used to detect PTPgamma expression in MCF-7 cells. To determine the response of MCF-7 cells to endocrine therapy, MCF-7 was treated with either 20 ng/ml KGF or 10 microM KGF-13 combined with 1, 3 and 5 microM of 4-hydroxytamoxifen (4OH-Tam). A non-radioactive cell proliferation assay was applied to determine the growth rate of MCF-7 cells. The results of real-time PCR and the cell proliferation assay were analyzed by Student's t-test and p-values of less than 0.05 were considered statistically significant.
RESULTS: Our data showed that KGF significantly suppressed ER-alpha, PR and PTPgamma expression in MCF-7 cells. KGF suppressed ER-alpha, PR and PTPgamma mRNA to a maximal inhibition at 20 ng/ml by 88%, 57% and 61%, respectively. Western blot analysis and immunohistochemical staining confirmed the down-regulation of ER-alpha, PR and PTPgamma by KGF in protein levels. Ten microM KGF-13 also decreased ER-alpha expression. Ten microM KGF-13 significantly decreased ER-alpha, PR and PTPgamma mRNA expressions by 51%, 57% and 67%, respectively. These KGF-13-mediated mRNA down-regulations were also observed in protein levels. In a cell proliferation assay, 4OH-Tam (3, 5 microM) induced MCF-7 cell death. KGF and KGF-13 alone did not stimulate MCF-7 cell growth. KGF significantly disrupted 4OH-Tam cell killing effects by 1.2- and 1.3-fold at 4OH-Tam concentrations of 3 microM and 5 microM, respectively. KGF-13 significantly disrupted 4OH-Tam cell killing effects by 1.2- and 1.7-fold at 4OH-Tam concentrations of 3 microM and 5 microM, respectively.
CONCLUSION: Our results suggested that not only ER-alpha and PR but also PTPgamma could be potential bio-makers for growth factor-induced endocrine resistant in breast cancer. KGF might increase the endocrine resistance via decreasing ER-alpha, PR and PTPgamma as well. Moreover, the functional analysis of KGF-13 implied possible applications of using short receptor-binding peptides derived from intact KGF as breast cancer therapeutic agents. Thus, our experimental data provided evidence of KGF-induced anti-hormone resistance in human breast cancer and suggested novel strategies for breast cancer via interference with KGF signaling.

Furuta J, Nobeyama Y, Umebayashi Y, et al.
Silencing of Peroxiredoxin 2 and aberrant methylation of 33 CpG islands in putative promoter regions in human malignant melanomas.
Cancer Res. 2006; 66(12):6080-6 [PubMed] Related Publications
Aberrant methylation of promoter CpG islands (CGI) is involved in silencing of tumor suppressor genes and is also a potential cancer biomarker. Here, to identify CGIs aberrantly methylated in human melanomas, we did a genome-wide search using methylation-sensitive representational difference analysis. CGIs in putative promoter regions of 34 genes (ABHD9, BARHL1, CLIC5, CNNM1, COL2A1, CPT1C, DDIT4L, DERL3, DHRS3, DPYS, EFEMP2, FAM62C, FAM78A, FLJ33790, GBX2, GPR10, GPRASP1, HOXA9, HOXD11, HOXD12, HOXD13, p14ARF, PAX6, PRDX2, PTPRG, RASD1, RAX, REC8L1, SLC27A3, TGFB2, TLX2, TMEM22, TMEM30B, and UNC5C) were found to be methylated in at least 1 of 13 melanoma cell lines but not in two cultured normal melanocytes. Among these genes, Peroxiredoxin 2 (PRDX2) was expressed in normal melanocytes, and its expression was lost in melanomas with methylation. The loss of expression was restored by treatment of melanomas with a demethylating agent 5-aza-2'-deoxycytidine. In surgical melanoma specimens, methylation of PRDX2 was detected in 3 of 36 (8%). Furthermore, immunohistochemical analysis of PRDX2 showed that disappearance of immunoreactivity tends to associate with its methylation. PRDX2 was recently reported to be a negative regulator of platelet-derived growth factor signaling, and its silencing was suggested to be involved in melanomas. On the other hand, 12 CGIs were methylated in >or=9 of the 13 melanoma cell lines and are considered as candidate melanoma biomarkers.

Wang LS, Huang YW, Sugimoto Y, et al.
Conjugated linoleic acid (CLA) up-regulates the estrogen-regulated cancer suppressor gene, protein tyrosine phosphatase gamma (PTPgama), in human breast cells.
Anticancer Res. 2006 Jan-Feb; 26(1A):27-34 [PubMed] Related Publications
BACKGROUND: Conjugated linoleic acid (CLA), a naturally occurring compound found in ruminants products, has been shown to possess anticancer properties in vivo and in vitro. There are several CLA isomers in ruminant-produced foods, among which t10, c12-CLA and c9, t11-CLA are the most potent. Protein tyrosine phosphatase gamma (PTPgamma) has been implicated as a tumor suppressor gene in kidney and lung cancers. Our previous results indicated that estradiol-17beta (E2)-induced suppression of PTPgamma may play a role in mammary tumorigenesis.
MATERIALS AND METHODS: The effects of t10, c12-CLA and c9, t11-CLA on PTPgamma mRNA expression in human breast epithelial cells and stromal cells, isolated from surgical specimens of mammoplasty and breast cancer patients, were detected and quantified by RT-PCR RESULTS: The PTPgamma mRNA expression was lower in cancer than in normal breast cells. Both t10, c12-CLA and c9, t11-CLA significantly (p < 0.05) increased the PTPgamma mRNA levels in primary cultured normal breast epithelial cells, normal breast stromal cells and breast cancer epithelial cells, but not in breast cancer stromal cells. t10, c12-CLA appeared to be the most active isomer in estrogen receptor a (ERalpha)-positive human breast cancer epithelial cells.
CONCLUSION: The results indicate that dietary CLA might serve as a chemo-preventive and chemo-therapeutic agent in human breast cancers by up-regulating the estrogen-regulated tumor suppressor gene, PTPgamma expression.

Wu CW, Kao HL, Li AF, et al.
Protein tyrosine-phosphatase expression profiling in gastric cancer tissues.
Cancer Lett. 2006; 242(1):95-103 [PubMed] Related Publications
Protein phosphorylation is an important regulatory mechanism involved in signal transduction and cancers. In comparison to the extensive tyrosine-kinase oncogenesis research, there are only relatively few studies of protein tyrosine-phosphatase expression in cancers. The expression profile for tyrosine-phosphatases was investigated in gastric cancers using RT-PCR and molecular cloning. The present study showed a general PTP expression profile in gastric cancer tissues, with the identification of 22 distinct tyrosine-phosphatases. Following the examination of five PTPs (PTPRA, PTPRB, PTPRD, PTPRG and PTPRZ) using immunohistochemistry, strong association was observed between PTPRA/PTPRZ expression and gastric cancer progression including lymphovascular invasion and liver/peritoneal dissemination.

van Doorn R, Zoutman WH, Dijkman R, et al.
Epigenetic profiling of cutaneous T-cell lymphoma: promoter hypermethylation of multiple tumor suppressor genes including BCL7a, PTPRG, and p73.
J Clin Oncol. 2005; 23(17):3886-96 [PubMed] Related Publications
PURPOSE: To analyze the occurrence of promoter hypermethylation in primary cutaneous T-cell lymphoma (CTCL) on a genome-wide scale, focusing on epigenetic alterations with pathogenetic significance.
MATERIALS AND METHODS: DNA isolated from biopsy specimens of 28 patients with CTCL, including aggressive CTCL entities (transformed mycosis fungoides and CD30-negative large T-cell lymphoma) and an indolent entity (CD30-positive large T-cell lymphoma), were investigated. For genome-wide DNA methylation screening, differential methylation hybridization using CpG island microarrays was applied, which allows simultaneous detection of the methylation status of 8640 CpG islands. Bisulfite sequence analysis was applied for confirmation and detection of hypermethylation of eight selected tumor suppressor genes.
RESULTS: The DNA methylation patterns of CTCLs emerging from differential methylation hybridization analysis included 35 CpG islands hypermethylated in at least four of the 28 studied CTCL samples when compared with benign T-cell samples. Hypermethylation of the putative tumor suppressor genes BCL7a (in 48% of CTCL samples), PTPRG (27%), and thrombospondin 4 (52%) was confirmed and demonstrated to be associated with transcriptional downregulation. BCL7a was hypermethylated at a higher frequency in aggressive (64%) than in indolent (14%) CTCL entities. In addition, the promoters of the selected tumor suppressor genes p73 (48%), p16 (33%), CHFR (19%), p15 (10%), and TMS1 (10%) were hypermethylated in CTCL.
CONCLUSION: Malignant T cells of patients with CTCL display widespread promoter hypermethylation associated with inactivation of several tumor suppressor genes involved in DNA repair, cell cycle, and apoptosis signaling pathways. In view of this, CTCL may be amenable to treatment with demethylating agents.

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